The active form of vitamin D exerts its functions (such as regulation of calcium metabolism, inhibition of cell proliferation/induction of differentiation, regulation of inflammation/immune response, regulation of the cardiovascular system and hair cycle, etc.) via binding to vitamin D receptor (VDR). If these activities can be controlled, it is believed that vitamin D preparations are potential therapeutics for osteoporosis, malignant neoplasms, infectious diseases, autoimmune diseases, cardiovascular diseases, alopecia and so forth.
However, most of those compounds which have been synthesized and developed as pharmaceuticals so far are agonists with action spectra almost similar to those of the natural hormone. They have the problem of hypercalcemia, an adverse effect common to active vitamin D preparations, and this has limited their development as pharmaceuticals. Among them, alfacalcidol was developed as the first therapeutic for osteoporosis; subsequently, maxacalcitol and calcipotriene were developed clinically as topical therapeutics for psoriasis. Maxacalcitol exhibits pharmacokinetic tissue-selectivity, and its clinical application has been expanded as a therapeutic for secondary hyperparathyroidism. However, vitamin D preparations which have cell- or tissue-selectivity at the gene expression level (such as seen in selective estrogen receptor modulators of estrogen receptors) have not been developed yet. Further, several groups of compounds have been reported as vitamin D derivatives with VDR antagonist effect (Non-Patent Documents Nos. 1-3), but pharmaceutical development of them has not succeeded. On the other hand, a group of compounds called “non-secosteroid” found in totally synthesized substances as compounds with the activity of active vitamin D are now being developed as selective VDR modulators (Non-Patent Documents Nos. 4-8).
Conventional active vitamin D derivatives have been developed as VDR full agonists. When administered to human or animals, these derivatives increase blood calcium levels at the dose level where they exhibit their therapeutic effect. It is believed that the cause of hypercalcemia is the induction of expression of a calcium transporter gene in the small intestinal mucosa. This adverse effect (hypercalcemia) makes it difficult to use conventional active vitamin D derivatives safely in clinical scenes for treating diseases other than vitamin D deficiency such as rickets or osteomalacia. This is the reason why active vitamin D preparations could not be developed as therapeutics for osteoporosis in Europe and the United States; and this is also the reason why the development of vitamin D preparations as anticancer agents or immunomodulatory agents did not succeed. Therefore, the key to the development of active vitamin D preparations is to separate the blood calcium raising effect (calcium absorption enhancement effect in the small intestinal mucosa) from other effects. To date, no success has been reported in this separation. One of the reasons is considered as follows: in VDR full agonist-type derivatives developed so far, the surface structure of the activation function 2 (AF2) of ligand-bound VDR is similar to those of the conventional VDR agonists, and, thus, no selectivity will occur in the binding to various coactivators, corepressors, etc. (which are transcriptional coactivators). As a result, their activity cannot be expected to have tissue-selectivity.